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A strike against stroke?

Posted on 4 November 2010

A strike against stroke?

Strokes — bleeding or blocked blood vessels in the brain — are a major cause of disability, and most neuroscientists say the brain has little or no ability to repair itself afterwards: Dead neurons do not spring to life. They are not replaced, and losing the ability to talk to each other is irrevocable.

Relearning the activities of daily life can be a struggle after a stroke. The University of Cincinnati has tested a robotic brace to aid recovery. A drug that restores brain cells could reduce the need for this kind of retraining.

When a stroke cannot be prevented, damage is irreversible. Or so went the neuroscientific dogma.

But a mouse study being published today in Nature shows that suppressing a common brain chemical can boost neuronal repair after a stroke. The treatment focuses not on restoring neurons, but rather on restoring connections, so neurons located at the edge of the dead zone can talk to each other and go back to work.

Based on tests of walking ability, the mice regained 30 to 50 percent of their motor coordination. If this result can be repeated, it could represent a major step forward, as no drug is approved for helping restore communication between nerve cells after a stroke.

“Basically, we are upsetting a lot of dogma that says the brain does not repair itself or recover, that there is no formation of new connections,” says study leader S. Thomas Carmichael, a professor of neurology and stroke specialist at the University of California at Los Angeles. “My lab is one of those that has showed that this is not true, and that has opened interesting molecular and cellular questions about what happens to regenerate the brain.”

Begging for an explanation

The research was rooted in some facts that did not jibe with the “no repair” dogma, Carmichael says. “Most strokes get a little better, and some get quite a bit better, in the weeks after the stroke. So our question is what events lead to this repair and recovery in the brain, and why they are limited.”

Several processes could explain these small recoveries, Carmichael says:

Neurons adjacent to the damage may sprout new connections

New neurons may form to replace those that die during the stroke

Immature glial (support) cells may mature into new glia that help repair neurons

GABA acts at synapses and elsewhere

In a mouse study, blocking the inhibitory brain chemical GABA away from the synapse was key to recovery after a stroke.

Brain cells are under both positive and negative controls; some chemicals make them more excitable, and others dampen their excitation. The study reported today was designed to test whether blocking a major inhibitory chemical would help neurons return to work after a stroke.

Just as two negatives make a positive, blocking an inhibitory chemical can stimulate a nerve cell.

The study concerned GABA, the major inhibitory compound in the brain. GABA released at a synapse, where neurons connect with each other, causes other neurons to briefly be less excitable. In the 1990s, an “extra-synaptic” receptor for the same compound, GABA, was found elsewhere on the nerve cell. “This is a whole separate group of GABA receptors that are on the cell body,” says Carmichael. “They don’t respond to GABA released into the synapse, but to GABA that spills over.”

Because these receptors are built differently, they can be blocked without affecting the synaptic GABA, says Carmichael.

During the experiment, Carmichael and colleagues used chemical or genetic mechanisms to block extra-synaptic GABA, and found that the mice recovered 30 to 50 percent of their motor coordination in various tests.

Neurons in the area around the injury started conversing once again, but only if they had been treated with the GABA inhibitor.

Courtesy S. Thomas Carmichael, UCLA

After a stroke, mice received three treatments. “Foot faults” measured their coordination; mice that got the experimental drug L655,708 were more coordinated than untreated mice.

Red: Stroke alone.

Blue: Stroke + GABA-inhibiting compound

Green: GABA-inhibiting compound (no stroke)

A promising drug?

Many drugs cannot enter the brain, but Carmichael says the oddly-named L655,708 can do so. And since it’s in early-stage human trials, it has already satisfied preliminary safety standards. More important, no other drug treatment has been able to put intact, but “stunned,” neurons back to work following a stroke, Carmichael says.

In essence, the treatment seems to “change the set point of neurons,” Carmichael says, making them more excitable — without affecting the synapse. “Inhibiting or blocking all inhibition of synaptic signaling would put you to sleep or give you a seizure, and neither is desirable after a stroke. The nice thing about this receptor is that it is involved in a completely different situation.”

After a stroke, blocking the brain chemical GABA allowed neurons near the injury to converse once again.

“The research is both important and relevant,” commented Matthew B. Jensen, an assistant professor in the Comprehensive Stroke Program at the University of Wisconsin-Madison. “Post-stroke disability is a major public health problem, and we need to better understand the limitations for recovery of the nervous system after injury to be able to design effective treatments.”

“The study matters because it suggests a new target for treatments to improve stroke recovery,” Jensen added, although it is not completely clear that the drug acted solely in the area near the stroke, or also elsewhere in the nervous system.

The 30 to 50 percent improvement is “dramatic, an impressive recovery,” says Carmichael. Treatment for strokes focuses on restoring blocked blood flow, but “If you look at stroke literature, there are no drugs that promote recovery” of lost function.

But this is only one study, as Carmichael admits. “We have done this in one lab, and somebody has to replicate these findings.”

Once that happens, it should be time to test the drugs in stroke patients. Although mice are not people, “At that point, we will have done all we can with a non-human model.”